Lack of medication adherence has been shown to correlate strongly with relapse and re-hospitalization during schizophrenia maintenance treatment. With each successive relapse, the patient's long-term prognosis deteriorates and previous levels of functioning are rarely achieved. Patient non-adherence also places an additional burden on the US healthcare system, which is estimated at $2.3 Billion per year. Long-acting antipsychotics provide substantial benefits to patients by improving medication adherence. Currently, the only available long acting formulation of olanzapine is Zyprexa RelprevvTM (ZR), a 2-4 week depot injection. Unfortunately, the adoption of this product has been very limited due to concerns regarding its safety and efficacy. ZR carries the risk of post-injection delirium/sedation syndrome (PDSS), a serious condition which includes heavy sedation, coma, and delirium after injection. Patients need to be observed for 3 hours post-injection in a healthcare facility with emergency response services, and be accompanied from the facility to their destination. It takes 5-6 months for the systemic concentration of olanzapine to reach 100% of the intended level, and the steady-state peak-to-trough plasma concentration fluctuates by a factor of 4 for the dose interval, compared to 1.85 for oral. Similar to other depots, ZR cannot be withdrawn after administration. To move beyond the 2-4 week limit and substantially improve the safety profile of the product, this effort focuses on developing a small implant that releases olanzapine at a constant rate for 3 months. The proposed product is a matchstick-sized reservoir implanted during a simple, 15 minute, in-office procedure with local anesthesia. The benefits of such a product include eliminating the risk of PDSS, allowing for withdrawal of the medication if needed due to Adverse Effects, and delivering the medication in more favorable PK profile. The proposed product will also extend the release from 2-4 weeks to 3 months, further improving medication adherence and clinical outcomes. Although some subcutaneous implant technologies already exist, none of them is suitable for the delivery of olanzapine. Results of recent studies show that 86% of physicians and 50% of patients support the use of implants in this disease area. The technology is based on a unique formulation; a mixture of olanzapine and polylactic/polyglycolic (PLGA) polymers. The polymers produce weak, soluble acids over time as they hydrolyze, and, in doing so, promote the passive outward diffusion of olanzapine. The solubility of olanzapine is greatly enhanced upon protonation by acids, and thus the concentration gradient driving flux is greater under the acidic conditions provided by constant polymer hydrolysis within the reservoir.The technology has been validated preclinically with another drug (risperidone), which is expected to enter the clinic later this year. The current effort will test multiple formulations based on this technology in vitro and in vivo. The ultimate goal of this study is to show favorable PK and local tolerance and thus complete the preclinical proof-of-concept for the proposed olanzapine system.